Professor-Assistente
de Anestesiologia, MD, Facharzt Division of Anesthesia and Surgical ICU, King
Abdullah University Hospital, Faculty of Medicine, Jordan University of Science
and Technology, Irbid, Jordan

Propofol is a commonly used agent for the induction of general
anesthesia, especially for outpatient surgical procedures. The
pain on injection is still the major problem with propofol. Many
methods have been used to prevent or to alleviate pain on
injection caused by propofol such as applying propofol in
different temperature 1-4, lidocaine mixed with
propofol 5,6, lidocaine pretreatment without
7 or with tourniquet 8. Furthermore,
multiple agents have been administered such as metoclopramide
9, nitroglycerin 10, procaine
11, prilocaine 12, opioids 7 and
ketorolac 13,14 with variable results. Recent and
early studies showed that temporary venous occlusion following
premedication with lidocaine did indeed diminish the intensity of
pain 15,16.

The purpose of this study was to assess the efficacy of the
pretreatment with lidocaine and lidocaine mixed with fentanyl and
IV paracetamol on diminish pain associated with the injection of
propofol after temporary venous occlusion using an increased
volume to 4 mL instead of the commonly used 2 mL.

METHODS

After ethical approval
by the local Research Ethics Committee and after obtaining a written informed
consent from all patients, 200 ASA physical status IIII
aged 2173
yr patients scheduled for elective gynecological, urological or general surgical
procedures were entered into this double-blind, randomized, placebo-controlled
study.

Exclusion criteria were refusal of consent, heart failure,
renal failure and liver dysfunction. Patients taking sedatives,
analgesics, central nervous system (CNS) depressants or
anti-seizure medication, or with a history of intolerance or
adverse reactions to the medications used in the study were also
excluded from the study.

A total of 200 patients (50 patients each group) were
randomized by a sealed envelope system to be pretreated either
with 4 mL lidocaine 1% (Group L) or with 2 mL lidocaine 2% mixed
with 2 mL fentanyl (Group LF) or 4 mL IV paracetamol (Group R) or
with 4 mL isotonic sodium chloride solution as placebo (Group P)
followed by propofol 2.5 mg.kg-1 after 60 seconds of
venous occlusion. On arrival to the anesthesia room all patients
received a 20G intravenous catheter in the dorsum of the hand.
Standard monitoring was used throughout the study and the
surgical procedure, including non-invasive blood pressure, heart
rate and pulse oximetry.

The venous occlusion of 60s for all groups was done on the arm
at a distance of about 8 cm proximal the anticubital fosse using
a 2.5 cm wide rubber tourniquet.

After 60 seconds the tourniquet had been released 2.5
mg.kg-1 propofol were injected at rate of 0.5
mL.s-1.

The patients of placebo group (n = 50) received 4 mL 0.9%
normal saline. The patients of Group L (n = 50) were pretreated
with 4 mL lidocaine 1% (total = 40 mg). The patients of Group LF
(n = 50) were pretreated with 2 mL lidocaine 2% (total = 40 mg)
and 2 mL fentanyl (total = 100 µg) while the patients of
Group R (n = 50) were pretreated with 4 mL paracetamol (total =
40 mg). Four different Anesthesiology residents of the last year
of training were involved in this study. The anesthesiologist,
who was blind to the content of the study syringe, assessed the
pain on injection associated with propofol. These included
movement of hand, spontaneous verbal expressions of pain,
frowning, and moaning during the injection.

This study proposes that the pretreatment with increased
volume of lidocaine and mixing the lidocaine with fentanyl and
paracetamol after temporary venous occlusion will diminish the
pain on injection associated with propofol.

Data are presented as mean and standard deviation or as group
percentages. Statistical evaluation was done with the Students
t and Chi-square tests, incorporating Fishers Exact test
where appropriate. Differences were considered statistically
significant at p < 0.05.

Statistical calculations were performed using the Statistical
Package for the Social Sciences Software Program version 13
(SPSS®, Inc).

RESULTS

Of the 200 patients
enrolled in this study, 50 patients were randomly assigned to each treatment
group. The groups did not differ in age, gender, ASA physical status, bodyweight
and height (Table I).

Propofol injection triggered pain in 32 patient's in Group P
(64%), 16 patients in Group L (32%), 15 patients in Group LF
(30%) and 23 patients in Group R (46%).

Compared with the placebo group, there was significantly less
pain noted by the patients of Group L (36% pain free versus 68%;
p < 0.05), the patients of Group LF (36% pain free versus 70%;
p < 0.05) and the patients of Group R (36% pain free versus
54%; p < 0.05).

The tourniquet isolates the arm veins from the rest of the
circulation. This is useful for studying the peripheral actions
of a drug in the absence of its central effect 8.

The mechanism by which propofol causes pain on injection
remains unclear 14, although Scott et al.
17 have suggested an enzyme cascade, possibly the
kallekrein-kinin cascade. This suggestion was supported by Iwama
et al. 17, who demonstrated that the pretreatment with
kallekrein inhibitor inhibited the propofol injection pain.

The main finding of this study is that intravenous
pretreatment with lidocaine; IV paracetamol and mixture of
lidocaine with fentanyl reduced the pain caused by intravenous
propofol injection.

Lidocaine and mixture of lidocaine with fentanyl were
effective in reducing the incidence of propofol injection pain,
although the difference did not reach statistical
significance.

Paracetamol was also effective in reducing the incidence of
propofol injection pain, but significantly less than lidocaine
and mixture of lidocaine with fentanyl.

The incidence of pain on injection of propofol has been
reported to be 70% 15,19. In this study 64% of the
subjects in the placebo group complained of pain at the site of
injection. This correlated with the results of other studies
20,21.

Lidocaine, a local anesthetic, reversibly blocks peripheral
nerve pathways through the action on excitable membranes in the
arm 8. It was found a diminished incidence of pain
with lidocaine 40 mg IV pretreatment injected as a Bier's block.
In this study 32% of the patients in the lidocaine group
complained of pain following the injection of propofol. This
finding is consistent with the results of Schaub et al.
15.

The primary clinical effect of fentanyl as an opioid is
related to its interaction with opiate receptors centrally and
with larger dose could have a local anesthetic effect
22,23.

To use this local effect of fentanyl it was mixed with
lidocaine in Lidocaine-Fentanyl group. It was found in this study
that the effectiveness of lidocaine mixed with fentanyl in
reducing propofol injection pain is similar to that of
lidocaine.

Perfalgan® solution (10 mg.mL-1)
contains the active ingredient paracetamol for the short-term
treatment of moderate pain and for the short-term treatment of
fever 24. In this study it was aimed to use the
analgesic effect of paracetamol intravenously given before
propofol injection after 60 seconds of venous occlusion. In the
group pretreated with IV paracetamol 23 patients (46%) complained
of pain associated with propofol injection.

In conclusion, there was a significant superiority of IV
paracetamol compared to placebo whereas lidocaine and lidocaine
mixed with fentanyl significantly reduced propofol injection pain
compared to IV paracetamol and to placebo.

The addition of fentanyl to lidocaine does not seem to be a
good method to increase the effectiveness of lidocaine in
reducing the propofol injection pain.